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Methadone is a mu (µ) opioid receptor agonist used clinically in adults and children to manage opioid use disorder, neonatal abstinence syndrome, and acute and chronic pain. It is typically marketed as a racemic mixture of R- and S-enantiomers. R-methadone has 30-to 50-fold higher analgesic potency than S-methadone, and S-methadone has a greater adverse effect (prolongation) on the cardiac QTc interval. Methadone undergoes stereoselective metabolism. CYP2B6 is the primary enzyme responsible for catalyzing the metabolism of both enantiomers to the inactive metabolites, S- and R-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (S- and R-EDDP). Genetic variation in the CYP2B6 gene has been investigated in the context of implications for methadone pharmacokinetics, dose, and clinical outcomes. Most CYP2B6 variants result in diminished or loss of CYP2B6 enzyme activity, which can lead to higher plasma methadone concentrations (affecting S- more than R-methadone). However, the data do not consistently indicate that CYP2B6-based metabolic variability has a clinically significant effect on methadone dose, efficacy, or QTc prolongation. Expert analysis of the published literature does not support a change from standard methadone prescribing based on CYP2B6 genotype (updates at www.cpicpgx.org).
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OBJECTIVES: The objective of this integrative review is to call attention to the limited published literature on professional identity formation (PIF) in students who hold marginalized identities and to promote more inclusive PIF models. FINDINGS: A person's identity is complicated and PIF is a dynamic and continuous lifelong process. A foundational component to PIF is for students to integrate their developing professional identity with their existing selves. Most PIF theoretical frameworks used in health education were created with a dominant culture lens and during a time when most professionals in practice were cisgendered, White, and/or male. These frameworks do not consider ways in which PIF may differ in learners who hold marginalized identities nor the influence that their marginalized identities may have on facilitators and barriers to their PIF journeys. SUMMARY: PIF is a growing area of focus in pharmacy education and scholarship. To effectively support PIF for each member of a diverse student body, pharmacy educators must recognize the limitations of existing PIF theoretical frameworks owing to the historical exclusion of considerations of students' and practitioners' marginalized identities as a layer of professional identity, especially in the context of historical injustices. As members of the pharmacy Academy begin or continue to explore PIF in pharmacy education, they must be mindful and intentional about how they account for the impact that students' marginalized identities may have on their PIF.
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Educación en Farmacia , Estudiantes de Medicina , Humanos , Masculino , Identificación Social , Educación en SaludRESUMEN
This chapter deals with practical considerations on key issues such as choosing an enzyme source, determining linear conditions, and choosing appropriate substrate and organic solvent concentrations. Practical solutions for working with limited resources and carrying out inhibition experiments are also addressed. Thus, after reading this chapter, the novice reader should have a better idea of how to design, develop, and interpret basic experiments using drug metabolism enzymes.
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Enzimas/metabolismo , Hepatocitos/metabolismo , Preparaciones Farmacéuticas/metabolismo , Animales , Hepatocitos/enzimología , Humanos , Cinética , Lisosomas/enzimología , Proyectos de InvestigaciónRESUMEN
The HIV type-1 nonnucleoside reverse transcriptase inhibitor, efavirenz, is widely used to treat HIV type-1 infection. Efavirenz is predominantly metabolized into inactive metabolites by cytochrome P450 (CYP)2B6, and patients with certain CYP2B6 genetic variants may be at increased risk for adverse effects, particularly central nervous system toxicity and treatment discontinuation. We summarize the evidence from the literature and provide therapeutic recommendations for efavirenz prescribing based on CYP2B6 genotypes.
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Benzoxazinas/farmacología , Citocromo P-450 CYP2B6/genética , Infecciones por VIH , VIH-1 , Pruebas de Farmacogenómica/métodos , Alquinos , Fármacos Anti-VIH/farmacología , Ciclopropanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Humanos , Farmacogenética , Guías de Práctica Clínica como AsuntoRESUMEN
Diabetes mellitus is a worldwide problem with an immense pharmacoeconomic burden. The multifactorial and complex nature of the disease lends itself to personalized pharmacotherapeutic approaches to treatment. Variability in individual risk and subsequent development of diabetes has been reported in addition to differences in response to the many oral glucose lowering therapies currently available for diabetes pharmacotherapy. Pharmacogenomic studies have attempted to uncover the heritable components of individual variability in risk susceptibility and response to pharmacotherapy. We review the current pharmacogenomics evidence as it relates to common oral glucose lowering therapies and how they can be utilized in the management of polygenic and monogenic forms of diabetes. Evidence supports the use of genetic testing and personalized approaches to the treatment of monogenic diabetes of the young. The data are not as robust for the current application of pharmacogenetic approaches to the treatment of polygenic type 2 diabetes mellitus, but there are suggestions as to future applications in this regard. We reviewed pertinent primary literature sources as well as current evidence-based guidelines on diabetes management.
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Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/terapia , Manejo de la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Medicina de Precisión/estadística & datos numéricos , Diabetes Mellitus Tipo 2/diagnóstico , Humanos , Hipoglucemiantes/uso terapéutico , Medicina de Precisión/tendenciasRESUMEN
OBJECTIVES: Genetic factors contribute considerably toward variability in warfarin dose requirements and are important in the dose-titration phase; their effects on the stability of anticoagulation later in therapy are not known. METHODS: Using deidentified electronic medical records linked to a DNA-biobank, we studied 140 African-Americans and 943 European-Americans after the warfarin dose-titration phase. We genotyped 12 single nucleotide polymorphisms in genes (CYP2C9, VKORC1, CYP4F2, GGCX, EPHX1, CALU) associated with altered warfarin dose requirements and tested their associations with international normalized ratio variability (INRVAR) and percent time in therapeutic range in European-Americans and African-Americans. RESULTS: One allele copy of rs2108622 in CYP4F2 was associated with a 15% [95% confidence interval (CI): 1-26, P=0.03] decrease in the median INRVAR in European-Americans. In African-Americans, GGCX variants rs11676382 and rs699664 were associated with 4.16-fold (95% CI: 1.45-11.97, P=0.009) and 1.50-fold (95% CI: 1.07-2.08, P=0.02) changes in the median INRVAR per variant allele copy, respectively; rs11676382 was also significantly associated with a 23.19% (95% CI: 5.89-40.48, P=0.01) decrease in time in therapeutic range. The total variation in INRVAR explained by both clinical factors and rs2108622 was 5.2% for European-Americans. In African-Americans, the inclusion of GGCX variants rs11676382 and rs699664, and the CYP2C9*8 variant rs7900194 explained â¼29% of the variation in INRVAR. CONCLUSION: The stability of anticoagulation after the warfarin dose-titration phase is differentially affected by variants in CYP4F2 in European-Americans and GGCX loci in African-Americans.
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Anticoagulantes/administración & dosificación , Negro o Afroamericano/genética , Variantes Farmacogenómicas , Warfarina/administración & dosificación , Población Blanca/genética , Adulto , Anciano , Anciano de 80 o más Años , Proteínas de Unión al Calcio/genética , Ligasas de Carbono-Carbono/genética , Citocromo P-450 CYP2C9/genética , Familia 4 del Citocromo P450/genética , Epóxido Hidrolasas/genética , Femenino , Humanos , Relación Normalizada Internacional , Masculino , Persona de Mediana Edad , Vitamina K Epóxido Reductasas/genéticaRESUMEN
Aim: Simvastatin is a lactone prodrug that exists in equilibrium with its active hydroxyacid through a process mediated by UGT1A enzymes. The UGT1A locus has been associated with simvastatin response and disposition in humans. Therefore, we fine-mapped the UGT1A locus to identify genetic variations contributing to simvastatin disposition and response variability. Methods: Using de-identified electronic medical records linked to a DNA biobank, we extracted information about dose and low-density lipo-protein cholesterol (LDL-C) concentrations for patients who received more than two different doses of simvastatin. Pharmacodynamic measures of simvastatin potency and efficacy were calculated from dose-response curves (E0 = baseline LDL-C, ED50 = dose yielding 50% maximum response, and Emax = maximum decrease in LDL-C) in 1100 patients. We selected 153 polymorphisms in UGT1A1 and UGT1A3 for genotyping and conducted genotype-phenotype associations using a prespecified additive model. Results: Two variants in UGT1A1 (rs2003569 and rs12052787) were associated with Emax (p = 0.0059 and 0.031, respectively; for rs2003569 the mean Emax was 59.3 ± 23.0, 62.0 ± 22.4, and 69.7 ± 24.8 mg/dl, for patients with 0, 1 or 2 copies of the minor A allele, respectively). When stratified by race, the difference in response was greater in African-Americans than in European Americans. Rs2003569 was also negatively associated with total serum bilirubin levels (p = 7.85 × 10-5). Four rare SNPs were nominally associated with E0 and ED50. Conclusion: We identified a UGT1A1 promoter variant (rs2003569) associated with simvastatin efficacy. Original submitted 26 March 2014; Revision submitted 26 August 2014.
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At some point, anyone with knowledge of drug metabolism and enzyme kinetics started out knowing little about these topics. This chapter was specifically written with the novice in mind. Regardless of the enzyme one is working with or the goal of the experiment itself, there are fundamental components and concepts of every experiment using drug metabolism enzymes. The following case studies provide practical tips, techniques, and answers to questions that may arise in the course of conducting such experiments. Issues ranging from assay design and development to data interpretation are addressed. The goal of this section is to act as a starting point to provide the reader with key questions and guidance while attempting his/her own work.
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Pruebas de Enzimas/métodos , Enzimas/metabolismo , Preparaciones Farmacéuticas/metabolismo , Proyectos de Investigación , Interpretación Estadística de Datos , Pruebas de Enzimas/normas , Inhibidores Enzimáticos/farmacología , Humanos , Cinética , Modelos Lineales , Estándares de Referencia , Solventes/químicaRESUMEN
The Clinical Pharmacogenetics Implementation Consortium (CPIC) publishes genotype-based drug guidelines to help clinicians understand how available genetic test results could be used to optimize drug therapy. CPIC has focused initially on well-known examples of pharmacogenomic associations that have been implemented in selected clinical settings, publishing nine to date. Each CPIC guideline adheres to a standardized format and includes a standard system for grading levels of evidence linking genotypes to phenotypes and assigning a level of strength to each prescribing recommendation. CPIC guidelines contain the necessary information to help clinicians translate patient-specific diplotypes for each gene into clinical phenotypes or drug dosing groups. This paper reviews the development process of the CPIC guidelines and compares this process to the Institute of Medicine's Standards for Developing Trustworthy Clinical Practice Guidelines.
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Pruebas Genéticas/métodos , Farmacogenética/métodos , Guías de Práctica Clínica como Asunto , Genotipo , Humanos , Preparaciones Farmacéuticas/administración & dosificación , Fenotipo , Pautas de la Práctica en MedicinaRESUMEN
Statin medications are often prescribed to ameliorate a patient's risk of cardiovascular events due in part to cholesterol reduction. We developed and evaluated an algorithm that can accurately identify subjects with major adverse cardiac events (MACE) while on statins using electronic medical record (EMR) data. The algorithm also identifies subjects experiencing their first MACE while on statins for primary prevention. The algorithm achieved 90% to 97% PPVs in identification of MACE cases as compared against physician review. By applying the algorithm to EMR data in BioVU, cases and controls were identified and used subsequently to replicate known associations with eight genetic variants. We replicated 6/8 previously reported genetic associations with cardiovascular diseases or lipid metabolism disorders. Our results demonstrated that the algorithm can be used to accurately identify subjects with MACE and MACE while on statins. Consequently, future e studies can be conducted to investigate and validate the relationship between statins and MACE using real-world clinical data.
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Metabolites in safety testing have gained a lot of attention recently. Regulatory agencies have suggested that the kinetics of preformed and in vivo-formed metabolites are comparable. This subject has been a topic of debate. We have compared the kinetics of in vivo-formed with preformed metabolites. trans-3,5,4'-Trihydroxystilbene [trans-resveratrol (RES)] and its two major metabolites, resveratrol-3-sulfate (R3S) and resveratrol-3-glucuronide (R3G) were used as model substrates. The pharmacokinetics (PK) of R3S and R3G were characterized under two situations. First, the pharmacokinetics of R3S and R3G were characterized (in vivo-formed metabolite) after administration of RES. Then, synthetic R3S and R3G were administered (preformed metabolite) and their pharmacokinetics were characterized. PK models were developed to describe the data. A three-compartment model for RES, a two-compartment model for R3S (preformed), and an enterohepatic cycling model for R3G (preformed) was found to describe the data well. These three models were further combined to build a comprehensive PK model, which was used to perform simulations to predict in vivo-formed metabolite kinetics. Comparisons were made between in vivo-formed and preformed metabolite kinetics. Marked differences were observed in the kinetics of preformed and in vivo-formed metabolites.
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Glucurónidos/farmacocinética , Estilbenos/farmacocinética , Sulfatos/farmacocinética , Animales , Área Bajo la Curva , Biotransformación , Glucurónidos/administración & dosificación , Glucurónidos/sangre , Semivida , Inyecciones Intraarteriales , Masculino , Tasa de Depuración Metabólica , Ratones , Ratones Endogámicos C57BL , Modelos Biológicos , Resveratrol , Estilbenos/administración & dosificación , Estilbenos/sangre , Sulfatos/administración & dosificación , Sulfatos/sangreRESUMEN
Trans-3,5,4'-trihydroxystilbene (trans-resveratrol, RES) exhibits very low bioavailability due to extensive conjugative metabolism. Whether RES metabolites exhibit pharmacologic activity is of great interest. The present study aimed at synthesis of monoconjugates of RES - the 3- and 4' monosulfates (R3S and R4'S), and the 3- and 4' monoglucuronides (R3G and R4'G). Synthesis, purification, and yield are described. Synthesized metabolites were utilized to develop a sensitive LC-MS(n) assay for direct quantitation of all analytes. The assay was validated for intra- and inter-day precision and accuracy. Synthesis of RES conjugates and development and validation of a sensitive bioanalytical assay were applied to pharmacokinetic evaluation of RES and its circulating monoconjugates in C57BL mice. The study is a first report of direct quantitation of RES monosulfates and monoglucuronides. These results will aid in characterizing the disposition of RES and its major or active metabolites in vivo.
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Cromatografía Liquida , Glucurónidos/síntesis química , Glucurónidos/farmacocinética , Espectrometría de Masa por Ionización de Electrospray , Estilbenos/síntesis química , Estilbenos/farmacocinética , Sulfatos/síntesis química , Sulfatos/farmacocinética , Espectrometría de Masas en Tándem , Animales , Disponibilidad Biológica , Biotransformación , Cromatografía Liquida/normas , Glucurónidos/administración & dosificación , Glucurónidos/sangre , Inyecciones Intraarteriales , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Estándares de Referencia , Reproducibilidad de los Resultados , Resveratrol , Espectrometría de Masa por Ionización de Electrospray/normas , Estilbenos/administración & dosificación , Estilbenos/sangre , Sulfatos/administración & dosificación , Sulfatos/sangre , Espectrometría de Masas en Tándem/normasRESUMEN
AIMS: The only FDA approved medication for colorectal cancer (CRC) prevention is celecoxib. Its adverse effects underline the need for safer drugs. Polyphenols like resveratrol are in clinical trials for this purpose. This study aimed at examining effects of resveratrol alone and in combination with curcumin or chrysin on UGT induction in Caco-2 cells. Phytochemical combinations were selected using drug combination analyses of various anti-proliferation ratios of resveratrol+curcumin and resveratrol+chrysin. MAIN METHODS: Cell proliferation and UGT1A1 induction assays were carried out with individual polyphenols and combinations. Cell viability was determined with AlamarBlue assays. UGT1A1 mRNA was quantified via real time RT-PCR. UGT activity was determined with 4-methylumbelliferone (4MU) glucuronidation. KEY FINDINGS: Cell proliferation IC(50) estimates (± SE) for resveratrol, curcumin and chrysin were 20.8 ± 1.2, 20.1 ± 1.1 and 16.3 ± 1.3µM respectively. Combination of anti-proliferative effects showed additivity for resveratrol+chrysin and resveratrol+curcumin. Resveratrol at its IC(50) mediated a four-fold induction of UGT1A1 mRNA in a concentration independent manner. Chrysin at its IC(50) induced UGT1A1 expression seven-fold while Curcumin at its IC(90) mediated a two-fold induction. The 20 µM:40µ M resveratrol+curcumin and 20 µM :32 µM resveratrol+chrysin combinations mediated the greatest increases in mRNA expression (12 and 22 folds respectively). Significant increase in 4-MU glucuronidation was observed with combinations exhibiting maximal mRNA induction. SIGNIFICANCE: Phytochemical combinations can offer greater chemoprevention than single agents. These chemicals might offer safer options than present synthetic therapeutics for CRC prevention.
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Anticarcinógenos/farmacología , Curcumina/farmacología , Flavonoides/farmacología , Glucuronosiltransferasa/efectos de los fármacos , Estilbenos/farmacología , Anticarcinógenos/administración & dosificación , Células CACO-2 , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias Colorrectales/prevención & control , Curcumina/administración & dosificación , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Inducción Enzimática , Flavonoides/administración & dosificación , Glucurónidos/metabolismo , Glucuronosiltransferasa/biosíntesis , Humanos , Concentración 50 Inhibidora , ARN Mensajero/metabolismo , Resveratrol , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estilbenos/administración & dosificaciónRESUMEN
BACKGROUND: The uridine diphosphoglucuronosyltransferase (UGT) superfamily of enzymes catalyzes conjugative metabolism of numerous endobiotics and xenobiotics. Pharmacogenetic variation has been reported in almost all UGT family members. OBJECTIVE: To discuss tools available for evaluation of UGT polymorphisms. METHODS: Literature search was done to include all relevant UGT polymorphism studies involving in vitro methods. RESULTS/CONCLUSIONS: Studies evaluating associations between UGT genotype and resultant phenotype are described. Mammalian cells transfected with variant UGT isoforms or variant promoters have been developed. Human liver tissue genotyped for UGT genetic polymorphisms has been successfully used. New techniques to conduct these studies include RNA inhibition and development of transgenic animal models. Challenges and opportunities in the preclinical evaluation of UGT genotype-phenotype correlations are discussed.